PROJECT SUMMARY Obesity is a pandemic, gateway disease that significantly increases the risk of developing type 2 diabetes (T2D). This application focuses on delineating the function of oleoylethanolamide (OEA) as an enhancer of the insulinotropic and anorectic effects of glucagon-like peptide-1 receptor agonists (Glp1RA). Glp1RA represent a new class of T2D drugs that improve insulin sensitivity and promote weight loss. Therefore, therapeutic strategies that modulate specific Glp1RA signaling events may provide a novel approach for treating T2D and obesity. OEA is an endocannabinoid-like lipid that was recently shown to bind to Glp1 and augment Glp1- mediated cAMP production. We compared the effects of OEA on signaling mechanisms associated with insulin secretion and suppression of food intake (cAMP production, ?-arrestin recruitment, cellular glucose metabolism) in the presence of three Glp1RA (Glp1, Exendin-4 [Ex4], and Liralgutide [Lira]). We discovered that OEA modulates Glp1RA signaling events in a Glp1RA-specific manner. First, OEA enhances Glp1- mediated cAMP production and ?-arrestin recruitment. Second, OEA enhances Glp1- and Ex4-mediated glycolysis and mitochondrial respiration. Importantly, we demonstrate that peripheral administration of pre- mixed Ex4-OEA is more potently anorectic compared to either Ex4 or OEA alone. Based on these findings, we will use in vitro and in vivo approaches to define the impact of Glp1RA-OEA interactions on signaling events associated with enhanced insulin secretion and suppression of food intake and on these physiological endpoints themselves. We hypothesize that OEA binds to Glp1RA and modulates Glp1R signaling events that enhance cellular glucose metabolism, resulting in increased insulin secretion and more potent reductions in food intake compared to Glp1RA or OEA alone. Aim 1 will focus on determining the interaction dynamics between Glp1RA and OEA. Aim 2 will identify molecular signatures associated with Glp1RA-OEA combinations with a particular emphasis on mechanisms associated with insulin secretion and satiety (e.g., cellular glucose metabolism). Aim 3 will elucidate the impact of Glp1RA-OEA administration on insulin secretion and food intake. In the long-term, we seek to leverage this information towards the identification of more effective diabetes and weight loss therapies.